Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogen-activated protein (MAP) kinase cascades regulate a variety of cellular activities, including cell growth, proliferation, and apoptosis, and are reported to play a role in the actions of antidepressant treatment. There are a number of different classes of protein phosphatases that could influence the MAP kinase cascade. One of these, the MAP kinase phosphatase (MKP) family, is known to play a key role in dephosphorylation of activated MAP kinase. In the present study, we analyzed the expression of the MKP1, MKP2, and MKP3 isoforms in rat brain after electroconvulsive seizure (ECS), considered the most effective treatment for depression. In situ hybridization analysis demonstrates that ECS differentially regulates the expression of the MKP isoforms. Expression of MKP1 mRNA is robustly increased by acute ECS in the major cell layers of the hippocampus, including the dentate gyrus granule cell layer and the CA1 and CA3 pyramidal cell layers. In contrast, MKP2 is induced mainly in the dentate gyrus and MKP3 is preferentially increased in the CA1 and CA3 cell layers. In the prefrontal cortex, all three MKP isoforms are upregulated by acute ECS administration. Chronic ECS resulted in a similar pattern of induction for each of the MKP subtypes, demonstrating that there is little or no desensitization of the response to repeated ECS. The induction of MKP expression serves as negative feedback control for the MAP kinase cascades. Upregulation of MKP expression could dampen the actions of ECS, indicating that blockade of the MKPs could enhance the actions of antidepressant treatment.
...
PMID:Electroconvulsive seizures increase the expression of MAP kinase phosphatases in limbic regions of rat brain. 1549 35

Chronic exposure to alcohol modifies physiological processes in the brain, and the severe symptoms resulting from sudden removal of alcohol from the diet indicate that these modifications are functionally important. We investigated the gene expression patterns in response to chronic alcohol exposure (21-28 wk) in the rat nucleus tractus solitarius (NTS), a brain nucleus with a key integrative role in homeostasis and cardiorespiratory function. Using methods and an experimental design optimized for detecting transcriptional changes less than twofold, we found 575 differentially expressed genes. We tested these genes for significant associations with physiological functions and signaling pathways using Gene Ontology terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, respectively. Chronic alcohol exposure resulted in significant NTS gene regulation related to the general processes of synaptic transmission, intracellular signaling, and cation transport as well as specific neuronal functions including plasticity and seizure behavior that could be related to alcohol withdrawal symptoms. The differentially expressed genes were also significantly enriched for enzymes of lipid metabolism, glucose metabolism, oxidative phosphorylation, MAP kinase signaling, and calcium signaling pathways from KEGG. Intriguingly, many of the genes we found to be differentially expressed in the NTS are known to be involved in alcohol-induced oxidative stress and/or cell death. The study provides evidence of very extensive alterations of physiological gene expression in the NTS in the adapted state to chronic alcohol exposure.
...
PMID:Chronic alcohol exposure alters transcription broadly in a key integrative brain nucleus for homeostasis: the nucleus tractus solitarius. 1618 78

In neurons, a variety of extracellular stimuli are capable of inducing transcriptional events that underlie complex processes ranging from learning to disease. The mechanisms linking these long-lasting cellular modifications to behavior remain to be established. Here, we show by microarray analysis that hippocampal activation of glucagon-like peptide-1 receptor (GLP-1R), which is associated with improved learning and neuroprotection, results in suppression of the transcription factor DBP (albumin D-site-binding protein). Recombinant adeno-associated virus (rAAV) based gene expression of DBP in the hippocampus of adult rats caused upregulation of mRNAs encoding constituents of the molecular clock, and the DBP target gene, pyridoxal kinase. Behaviorally, DBP over expression inhibited spatial learning but not memory, and enhanced susceptibility to kainate-induced seizures. This phenotype was paralleled by the activation of MAP kinase in dendritic regions of hippocampal neurons in vivo. These data suggest that DBP may represent an important transcriptional link between GLP-1R activation and neuroplasticity in the hippocampus.
...
PMID:A novel role of circadian transcription factor DBP in hippocampal plasticity. 1625 26

Nicotine, acting through the neuronal nicotinic acetylcholine receptors (nAChRs), can induce seizures in mice. We aimed to study brain transcriptional response to seizure and to identify genes whose expression is altered after nicotine-induced seizures. Whole brains of untreated mice were compared with brains 1 h after seizure activity, using Affymetrix U74Av2 microarrays. Experimental groups included wild-type mice and both nicotine-induced seizure-sensitive and -resistant nAChR mutant mice. Each genotype group received different nicotine doses to generate seizures. This approach allowed the identification of significantly changed genes whose expression was dependent on seizure activity, nicotine administration, or both but not on the type of nAChR subunit mutation or the amount of nicotine injected. Significant expression changes were detected in 62 genes (P < 0.05, false discovery rate correction). Among them, gene ontology functional annotation analysis determined that the most significantly overrepresented categories were of genes encoding MAP kinase phosphatases, regulators of transcription and nucleosome assembly proteins. In silico bioinformatic analysis of the promoter regions of the 62 changed genes detected significant enrichments of 16 transcription regulatory elements (TREs), creating a network of transcriptional regulatory responses to seizures. The TREs for activating transcription factor and serum response factor were most significantly enriched, supporting their association with seizure activity. Our data suggest that nicotine-induced seizure in mice is a useful model to study seizure activity and its global brain transcriptional response. The differentially expressed genes detected here can help us to understand the molecular mechanisms underlying seizures in animal models and may also serve as candidate genes to study epilepsy in humans.
...
PMID:Expression changes in mouse brains following nicotine-induced seizures: the modulation of transcription factor networks. 1745 35

Stimulation paradigms that induce perforant path long-term potentiation (LTP) initiate phosphorylation of ERK1/2 and induce expression of a variety of immediate early genes (IEGs). These events are thought to be critical components of the mechanism for establishing the changes in synaptic efficacy that endure for hours or longer. Here we show that in mice, perforant path LTP can be induced using a standard protocol (repeated trains at 250 Hz), without accompanying increases in immunostaining for p-ERK1/2 or increased in expression of representative IEGs (Arc and c-fos). Signaling pathways capable of inducing ERK phosphorylation and IEG transcription are intact in mice because ERK phosphorylation differs strikingly in awake versus anesthetized mice, and IEG expression is strongly induced by electroconvulsive seizures. In pursuing the reasons for the lack of induction with LTP, we found that in rats, one of the stimulation paradigms used to induce perforant path LTP (trains at 250 Hz) also does not activate MAP kinase or induce IEG expression, despite the fact that the LTP induced by 250 Hz stimulation requires NMDA receptor activation and persists for hours. These findings indicate that there are different forms of perforant path LTP, one of which does not require MAP kinase activation or IEG induction. Moreover, these data demonstrate that different LTP induction paradigms do not have identical molecular consequences, which may account for certain discrepancies between previous studies.
...
PMID:A form of perforant path LTP can occur without ERK1/2 phosphorylation or immediate early gene induction. 1756 95

The ERK MAPK signalling pathway is a highly conserved kinase cascade linking transmembrane receptors to downstream effector mechanisms. To investigate the function of ERK in neurons, a constitutively active form of MEK1 (caMEK1) was conditionally expressed in the murine brain, which resulted in ERK activation and caused spontaneous epileptic seizures. ERK activation stimulated phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and augmented NMDA receptor 2B (NR2B) protein levels. Pharmacological inhibition of NR2B function impaired synaptic facilitation in area cornus ammonicus region 3 (CA3) in acute hippocampal slices derived from caMEK1-expressing mice and abrogated epilepsy in vivo. In addition, expression of caMEK1 caused phosphorylation of the transcription factor, cAMP response element-binding protein (CREB) and increased transcription of ephrinB2. EphrinB2 overexpression resulted in increased NR2B tyrosine phosphorylation, which was essential for caMEK1-induced epilepsy in vivo, since conditional inactivation of ephrinB2 greatly reduced seizure frequency in caMEK1 transgenic mice. Therefore, our study identifies a mechanism of epileptogenesis that links MAP kinase to Eph/Ephrin and NMDA receptor signalling.
...
PMID:ERK activation causes epilepsy by stimulating NMDA receptor activity. 1797 14

The granule cells of the dentate gyrus form the input stage of the hippocampal trisynaptic circuit and their function is strongly influenced by peptidergic systems. GPR54 is highly and discretely expressed in these cells. We have found that activation of GPR54 with kisspeptin-10 causes a rapid and large increase in the amplitude of excitatory synaptic responses in granule cells, without changing membrane properties. The effect was suppressed by the G-protein inhibitor GDP-beta-S and the calcium chelator BAPTA, and analysis of miniature EPSCs revealed an increase in mean amplitude but not event frequency, indicating that GPR54 and the mechanisms for enhancing EPSCs are postsynaptic, possibly involving changes in AMPA receptor number or conductance. The kisspeptin-induced synaptic potentiation was abolished by inhibitors of ERK1/2, tyrosine kinase, and CaMKII. RT-PCR experiments showed that KiSS-1 is expressed in the dentate gyrus. KiSS-1 mRNA was significantly increased by seizure activity in rats and when neuronal activity in organotypic hippocampal slice cultures was enhanced by kainate or picrotoxin, while mRNA for GPR54 remained essentially unchanged. These results suggest that kisspeptin may be locally synthesized and act as an autocrine factor. In separate experiments, hippocampal KiSS-1 mRNA in male rats was increased after gonadectomy. In summary, kisspeptin is a novel endogenous factor which is dynamically regulated by neuronal activity and which, in marked distinction from other neuropeptides, increases synaptic transmission in dentate granule cells through signaling cascades possibly linked to the MAP kinase system. This novel peptide system may play a role in cognition and in the pathogenesis of epilepsy.
...
PMID:The role of kisspeptin and GPR54 in the hippocampus. 1876 63

We have used laser-capture microdissection and microarray hybridization to characterize gene expression in the three principal neuron layers of rat hippocampus. Correlative and clustering analyses revealed all three layers to be easily differentiated from one another based on gene expression profile alone. A greater disparity in gene expression exists between dentate granule and pyramidal cell layers, reflecting phenotypic and ontological differences between those cell populations. Remarkably, the level of more than 45% of expressed transcripts was significantly different among the three neuron populations, with more than a third of those (>1,000 transcripts) being at least twofold different between layers. Even CA1 and CA3 pyramidal cell layers were dramatically different on a transcriptional level with a separate analysis indicating that nearly 20% of transcripts are differentially expressed between them. Only a small number of transcripts were specific for a given hippocampal cell layer, suggesting that functional differences are more likely secondary to wide-ranging expression differences of modest magnitude rather than very large disparities in a few genes. Categorical analysis of transcript abundance revealed concerted differences in gene expression among the three cell layers referable to specific cellular pathways. For instance, transcripts encoding proteins involved in glucose metabolism are most highly expressed in the CA3 pyramidal layer, which may reflect an underlying greater metabolic rate of these neurons and partially explain their exquisite vulnerability to seizure-induced damage. Conversely, transcripts related to MAP kinase signaling pathways and transcriptional regulator activity are prominent in the dentate granule cell layer, which could contribute to its resistance to damage following seizure activity by positioning these neurons to respond to external stimuli by altering transcription. Taken together, these data suggest that unique physiological characteristics of major cell layers, such as neuronal activity, neuronal plasticity, and vulnerability to neurodegeneration, are reflected in substantial transcriptional heterogeneity within the hippocampus.
...
PMID:Quantitative transcriptional neuroanatomy of the rat hippocampus: evidence for wide-ranging, pathway-specific heterogeneity among three principal cell layers. 1883 Sep 99

Different physiological and behavioral events activate transcription of Arc/Arg3.1 in neurons in vivo, but the signal transduction pathways that mediate induction in particular situations remain to be defined. Here, we explore the relationships between induction of Arc/Arg3.1 transcription in dentate granule cells in vivo and activation of mitogen-activated protein (MAP) kinase as measured by extracellular-regulated kinase 1/2 (ERK1/2) phosphorylation. We show that ERK1/2 phosphorylation is strongly induced in dentate granule cells within minutes after induction of perforant path long-term potentiation (LTP). Phospho-ERK staining appears in nuclei within minutes after stimulation commences, and ERK phosphorylation returns to control levels within 60 min. Electroconvulsive seizures, which strongly induce prolonged Arc/Arg3.1 transcription in dentate granule cells, induced ERK1/2 phosphorylation in granule cells that returned to control levels within 30 min. Following 30, 60, and 120 min of exploration in a novel complex environment, Arc/Arg3.1 transcription was activated in many more granule cells than stained positively for p-ERK at all time points. Although Arc/Arg3.1 transcription was induced in most pyramidal neurons in CA1 following exploration, very few pyramidal neurons exhibited nuclear p-ERK1/2 staining. Local delivery of U0126 during the induction of perforant path LTP blocked transcriptional activation of Arc/Arg3.1 in a small region near the injection site and blocked Arc/Arg3.1 protein expression over a wider region. Our results indicate that activation of Arc/Arg3.1 transcription in dentate granule cells in vivo is mediated in part by MAP kinase activation, but other signaling pathways also contribute, especially in the case of Arc/Arg3.1 induction in response to experience.
...
PMID:Assessment of the role of MAP kinase in mediating activity-dependent transcriptional activation of the immediate early gene Arc/Arg3.1 in the dentate gyrus in vivo. 2015 58

Under physiological conditions, L-aspartyl (L-Asp) and L-asparaginyl residues in proteins are spontaneously isomerized or racemized to D-aspartyl (D-Asp) or D,L-isoaspartyl (D,L-isoAsp) residue. These atypical Asp residues can interfere with protein activity and lead to disruption of cellular function. Protein L-isoaspartyl/D-aspartyl O-methyltransferase (PIMT) is a repair enzyme that initiates the conversion of L-isoAsp (or D-Asp) residues to L-Asp residues. PIMT-Deficient mice exhibit accumulation of L-isoAsp in several tissues and die from progressive epileptic seizures at a mean age of 42 days. However, the biological roles of PIMT are still largely unknown. To further our understanding of the function of this protein, we developed an assay to measure PIMT activity in cell lysates. Additionally, we generated PIMT-knockdown cells by stable transfection of HEK293 cells with PIMT small interfering (si) RNA. Northern blotting and immunoblot analysis revealed that PIMT mRNA and protein levels were significantly decreased in the knockdown cells. In addition, significant levels of proteins that contained isoAsp residues accumulated in these cells, and immunoblot analysis revealed that Raf-1, MEK, and ERK were hyperphosphorylated upon EGF stimulation compared to control cells. These results indicate that the ability to repair atypical Asp residues is important for normal MAP kinase signaling.
...
PMID:The role of protein L-isoaspartyl/D-aspartyl O-methyltransferase (PIMT) in intracellular signal transduction. 2056 50


<< Previous 1 2 3 Next >>

---